The invention relates generally to polynucleotides and polypeptides encoded thereby, as well as vectors, antibodies and recombinant methods for producing the polypeptides and polynucleotides.
The immune system of vertebrates is characterized by its ability to discriminate xe2x80x9cselfxe2x80x9d from xe2x80x9cnon-selfxe2x80x9d and to mount an appropriate, selective response to pathogens and other potentially harmful agents. Cell types involved in immune responses include lymphocytes known as B cells and T cells. Interactions between B cells and T cells are important for the propagation of full immune responses.
T cells must be activated in order to effect an immune response. T cell activation is thought to require two signals: an antigen-specific signal and a signal that is not antigen-specific. T cells can become activated by binding to B cells, particularly B cells which are themselves activated.
B cell-mediated activation of T cells is thought to be mediated, at least in part, by B7 proteins, which are expressed on the surface of B cells. B7 proteins are members of the immunoglobulin superfamily. They bind to activated T lymphocytes and provide regulatory signals for T lymphocyte cell growth and activation. (See, e.g., xe2x80x9cImmunobiologyxe2x80x94The Immune System in Health and Diseasexe2x80x9d, 1997, Third edition, chapter 7, Janeway, C. A. et al., eds., Garland Publishing Inc., New York.) Cell surface molecules on T cells which bind to B7 molecules include CTLA4 and CD28.
The present invention is based, in part, upon the discovery of BLAA polynucleotide sequences encoding novel members of the human B Lymphocyte Activation Antigen B7 family (henceforth xe2x80x9cBLAAxe2x80x9d).
In one aspect, the present invention involves an isolated nucleic acid molecule encoding a BLAA. This nucleic acid molecule may be a nucleotide that encodes a polypeptide having a sequence that is at least 95% identical to SEQ ID NO:2 or SEQ ID NO:6. Alternatively, it may be the complement of such a nucleic acid molecule.
In another aspect, this invention involves an oligonucleotide that is less than 100 nucleotides in length and contains at least 6 contiguous nucleotides of SEQ ID NO:1, 3, 5, 7, 8, 9, 10, 11, or 12. This oligonucleotide contains at least 6 contiguous nucleotides of a complement of SEQ ID NO:1, 3, 5, 7, 8, 9, 10, 11, or 12.
Another aspect of this invention relates to a vector containing an isolated nucleic acid molecule encoding a BLAA, as described above. In one embodiment, this vector is an expression vector. In another embodiment, this vector contains a regulatory element that is operably linked to the isolated nucleic acid molecule.
A further aspect of this invention involves an isolated polypeptide that is at least 80% identical to a polypeptide having an amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, or SEQ ID NO:6. In another embodiment of this aspect of the invention, the isolated polypeptide is at least 80% homologous to a fragment of a polypeptide having an amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, or SEQ ID NO:6. In this embodiment, the fragment contains at least 6 contiguous amino acids of SEQ ID NO:2, SEQ ID NO:4, or SEQ ID NO:6. Other embodiments of this aspect of the invention require that the isolated polypeptides of the invention be at least 80% homologous to a derivative, analog, or homolog of a polypeptide having an amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, or SEQ ID NO:6. Yet another embodiment involves an isolated polypeptide that is at least 80% identical to a naturally occurring allelic variant of a polypeptide having an amino acid sequence of SEQ ID NO:2, SEQ ID NO:4, or SEQ ID NO:6. This embodiment requires that the polypeptide be encoded by a nucleic acid molecule capable of hybridizing to a nucleic acid molecule of SEQ ID NO:1, SEQ ID NO:3, or SEQ ID NO:5, under stringent conditions.
Another embodiment of this invention involves an antibody that selectively binds to the polypeptide(s) described above. Further embodiments of this invention provide methods for (a) producing such polypeptide(s) by culturing a host cell under conditions in which the nucleic acid molecule is expressed; (b) detecting the presence of the polypeptide(s) in a sample by contacting the sample with a compound that selectively binds to the polypeptide(s) of the invention; and (c) modulating the activity of such polypeptide(s) by contacting a cell sample containing the polypeptide(s) of the instant invention with a compound that binds to the polypeptide(s) to modulate its activity.
Additionally, a method of detecting the presence of one of the nucleic acid molecules of this invention is also provided. This method involves contacting a sample with a compound that selectively binds to the polypeptide(s) of this invention and determining whether the compound bound to the polypeptide(s) is present in the sample.
Other embodiments of this invention include methods of treating or preventing immune response-associated disorders and therapeutic or prophylactic pharmaceutical compositions. Additionally, another aspect of this invention involves a kit containing therapeutically or prophylactically effective amounts of the pharmaceutical compositions provided for in the instant invention.
Another aspect of this invention involves the use of a therapeutic in the manufacture of a medicament for treating diseases associated with immune-response disorders. Another embodiment of this invention involves a method for screening for a modulator of activity, latency or predisposition to an immune response-associated disorder. In this embodiment, a test compound is administered to an animal at an increased risk for an immune response-associated disorder, measuring the expression of the polypeptide of the invention in the test animal, measuring polypeptide expression in a control animal, and comparing the expression in both animals.
Other embodiments of this invention include methods for determining the presence of or predisposition to a disease associate with altered levels of a BLAA polypeptide or a BLAA nucleic acid by measuring the amount of BLAA polypeptide or nucleic acid in a sample and comparing it to the amount present in a control sample. Yet other embodiments of this invention involve methods of treating a pathological state in a mammal by administering a BLAA polypeptide or a BLAA nucleic acid in amounts sufficient to alleviate the pathological state.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description and claims.